A lot of drugs of the new generation, primarily proteins, including recombinant proteins, and many other substances are not intended for administration using oral, inhalation and nasal routes. The drug delivery by means of injections is also not quite applicable; such proteins as, for example, interferons, interleukins and insulin rapidly get cleared out of the blood system and undergo proteolysis, including autolysis, tend to aggregate, adsorb and denature. Transdermal and transmucosal/transbuccal methods could be the most convenient routes to deliver these substances, all the more so transdermal and transmucosal/transbuccal delivery is much easier than the use of injections.
Theoretically, skin and mucous membranes can be viewed as a convenient route for the painless topical and systemic administration of multiple drug substances, but in practice the skin and mucous membranes act as a barrier, preventing penetration from the outside as well as the loss of water, electrolytes and resist the effects of chemical, physical and biological agents. Currently very few drug substances are delivered into the patients' bodies transdermally in clinical settings due to the low permeability of skin and mucous membranes.
The effectiveness of transdermal and transmucosal/transbuccal delivery of biologically active substances depends on their ability to penetrate skin and mucous membranes in the therapeutically effective amounts.
Maximum passive permeability through the concentration gradient-driven diffusion exists and is proved for the low molecular weight substances. However the diffusion through the skin of the large, particularly hydrophilic, molecules (molecular weight>500 kDa) is extremely low due to the skin (and mucous membranes) structure, primarily because of the outermost corneous skin layer—stratum corneum (SC). At the same time, many biopolymers, especially peptides and proteins, are effective therapeutic agents; however their delivery into the body through diffusion is practically impossible due to the fact that most of biologically active substances are not able to penetrate the barrier formed by the skin and mucous membranes. This is due to the physical and chemical properties of these substances. The majority of peptides, proteins and other biopolymers are high molecular weight hydrophilic substances that are not able to passively penetrate the mucous membranes and skin, especially the stratum corneum, the top layer of skin, as well as the underlying layers of skin and membranes, which only allow the molecules of low molecular weight lipophilic substances to pass through. For example, permeation efficiency of the charged substances through the stratum corneum is by two orders of magnitude lower than the permeation efficiency of the un-charged ones.
Methods of increasing skin permeability such as iontophoresis, microinjections, electroporation, sonophoresis, etc. allow transdermal and transmucosal/transbuccal delivery of large charged molecules, including peptides and proteins, which cannot pass through the stratum corneum and membranes by means of passive diffusion. The main advantages of these methods are a rapid onset of the drug action due to a short time period required for the pharmaceutical/cosmetic agents to reach their target, and also the ability to control the delivery by varying the strength and duration of exposure. Among the disadvantages are the patient's low compliance rate and contraindications for use of instrumental methods of drug delivery in a number of diseases.
Special substances that are called penetration enhancers (penetrators) are applied with a goal of reducing the impermeability of body barriers. Such substances facilitate the transdermal and transmucosal/transbuccal delivery of drug substances.
Many potential enhancers and technologies for transdermal delivery improvement are known, but, for a number of reasons, their efficiency is not satisfactory.
For instance, the early enhancers (for example, dimethyl sulfoxide and dimethyl formamide) were keratolytic agents. They irreversibly destroyed SC and accelerated skin penetration of a wide range of substances.
The serious drawbacks of such substances were toxicity, irritating properties and odor. Moreover, irreversible destruction of SC is not desirable.
The recently discovered enhancers, including propylene glycol, alcohols, surfactants and the like, whose application has fewer drawbacks, act by increasing the fluidity of the stratum corneum lipids. However, their effect is not sufficient for the effective transdermal delivery of biopolymers (Ashok K. Tiwary et al. 2007). Correspondingly, according to the well-known “500 Daltons rule”, even when using the chemical enhancers, the transdermal delivery of large (>500 Da) hydrophilic molecules through the intact skin into the bloodstream is almost impossible (Bos J. D. et al. 2000).
Another issue associated with the application of natural or recombinant biopolymers as the active agents relates to their stabilization during storage and use. First of all, this refers to peptides and proteins, particularly proteolytic enzymes, due to their rapid degradation caused by proteolysis and autolysis, which are the major obstacles to their use in medicine and cosmetology. In order to reduce the degradation of peptides they are stored as a dried powder and reconstituted before use.
It is desirable to produce ready-to-use forms since it will not require the assistance of highly qualified personnel during their application and increase the dosage precision.
At the same time it is necessary that the high-purity natural or recombinant biopolymers preserve their intact structural and functional properties for a long storage period, i.e. from several weeks up to several years in the ready-to-use forms. Thus, during the storage period, the molecules of the pharmaceutical/cosmetic products should be therapeutically and, ideally, biochemically inactive (which is particularly important in case of proteolytic enzymes).
If a modified polypeptide is used in order to achieve this goal, it is required to ensure that upon reaching the target, the modified molecules reinstate their original structure, thereby restoring their therapeutic properties.
It is obvious that the advances in the search for substances, which would allow overcoming these limitations, will significantly push forward towards the creation of the effective systems for transdermal and transmucosal/transbuccal delivery of the biologically active substances and expand the field of their application.